Dihydroxyalkenes are useful starting materials for numerous industrial chemical products including pharmaceuticals, agrochemicals, coatings, epoxyresins, and polyesters. For example, enantiomerically pure α,β-dihydroxyalkenes are useful intermediates for stereoselective transformations leading to pharmaceutically active materials such as HIV protease inhibitors and cyclosporins (see, for example, Ziegler et al. Tetrahedron: Asymmetry 1998, 9, 765). Dihydroxyalkenes also may be used to prepare epoxyolefins, such as 3,4-epoxy-1-butene, through a cyclodehydration reaction. Epoxyolefins have a rich chemistry and can further converted into a wide range of commercially valuable chemicals such as furans, alkylidene carbonates, cyclopropyl compounds, cyclobutyl derivatives, epoxyalkanes, and lactones (see, for example, Chimica Oggi, May 1996, pp. 17–18). Although 3,4-epoxy-1-butene is readily available though the direct oxidation of butadiene, the preparation of other epoxyolefins is difficult and generally requires multiple processing steps and expensive reagents.
The existing preparative methods for α,β-dihydroxyalkenes typically involve direct dihydroxylation of a diene. For example, Sharpless et al. J. Am. Chem. Soc. 1992, 114, 7570, report the asymmetric dihydroxylation of dienes using 3 molar equivalents of K3Fe(CN)6 as the oxidant in the presence of 1,4-bis(9-O-dihydroquinidinyl)phthalazine. Although yields and enantioselectivity were high, this process requires expensive and toxic reagents and exhibits poor selectivity between the olefinic groups of the diene. Alternatively, α,β-dihydroxyalkenes may be prepared by the epoxidation of dienes with hydrogen peroxide (see, for example, Espenson et al. Inorg. Chem. 1998, 37, 467) in the presence of a transition metal catalyst. The epoxyalkene is then hydrolyzed to produce the corresponding α,β-dihydroxyalkene. These processes often require multiple processing steps to obtain pure products and require the use of hydrogen peroxide which can be hazardous on a commercial scale. In addition, it is inherent in the above procedures that the starting diene possess the functional groups and structural features of the desired α,β-dihydroxyalkene products; thus, the preparation of the starting dienes is often difficult and expensive and limits the utility of these processes for the preparation of α,β-dihydroxy-alkenes with a variety of structures.
Enantiomerically enriched alkanediols also may be prepared by kinetic resolution methods involving hydrolysis of the corresponding epoxides in a method described by Jacobsen et al. Science 1997, 277, 936 or by hydrolysis of diol esters described in U.S. Pat. No. 5,445,963. Although such techniques provide a diol with high enantiomeric purity, overall yields are inherently limited to the amount of the desired stereoisomer present in the starting epoxide or ester, i.e., about 50% in a racemic mixture. Such low yields often make these processes uneconomical for commercial applications.
Olefin metathesis could potentially provide useful new α,β-dihydroxy-alkenes and derivatives, such as epoxyolefins and carbonates, using an inexpensive and available α,β-dihydroxyalkene, such as 3-butene-1,2-diol as a starting material. Traditional olefin methathesis processes, however, suffer from the disadvantage that olefins bearing functional groups, such as epoxy, amino, aldehydo, and hydroxyl rapidly deactivate the sensitive and expensive metathesis catalysts. For example, U.S. Pat. No. 5,952,533 discloses the metathesis of 3,4-epoxy-1-butene to give a bis-epoxy-olefin in less than 5% yields.
This problem restricts the use of the metathesis reaction to the preparation of relatively simple olefins with limited commercial applications.
During the past several years, olefin metathesis catalysts with increased tolerance to highly functionalized olefins, including carbohydrates and amino acids, have been described in PCT Application No. 02/00590, European Patent No. 1 022 282 A2; U.S. Pat. Nos. 6,306,988; 5,922,863; 5,831,108; and 4,727,215; U.S. patent application Ser. Nos. 09/849,100 and 09/891,144; Grubbs et al. Pure and Applied Chemistry 2002, 74, 7; Schrock et al. Tetrahedron 1999, 55, 8141; Herrmann et al. Ang. Chem. Intl. Ed. Engl. 1998, 37, 2490, and Grubbs et al. Tetrahedron 1998, 54, 4413. Although these catalysts show an increased tolerance toward various functional groups, hydroxyl groups in close proximity, for example adjacent or α- to the olefin, are reported to exhibit a strong retarding effect on catalyst activity (see, for example, Wagener et al. Macromolecules 1997, 30, 7363). To help counteract this retarding effect, protecting groups such as ethers and esters, frequently are attached to the hydroxyl groups prior to the metathesis step (see, for example, Hirama et al. Tetrahedron Letters 1999, 40, 5405). This approach, however, is unpredictable and highly dependent on the structure of the olefin and on the protecting group, (see, for example, Sarkar et al. Tetrahedron Letters 2002, 43, 2263). Even when such protecting groups are employed, the metathesis reaction often proceeds slowly and requires large amounts of catalyst for the reaction to proceed at practicable rates. Furthermore, the additional processing steps required to add and remove these protecting groups adds to the cost of the process and reduces product yields.
Thus, it is evident from the above that need exists for a flexible, efficient, and economical process for the preparation of α,β-dihydroxy-alkenes either as racemic mixtures or as enantiomerically enriched products. It also would be desirable to use an olefin metathesis process which utilizes a simple, inexpensive, and readily available α,β-dihydroxy-alkene or derivative thereof as a starting material. Finally, it would be desirable to convert the α,β-dihydroxyalkene products to the corresponding epoxyalkenes and alkanes and thus utilize the extensive chemistry and reactivity of the epoxide group for the preparation of pharmaceutical compounds, adhesives, and coatings.